Neurotransmitter Release at the Synapse
Concept Name
Synaptic Transmission
Genetic Loci
SNARE proteins: STX1A (7q11.23), SNAP25 (20p12.2), VAMP2 (17p13.1). Mutations in SNAP25 are associated with epilepsy and intellectual disability.
Intracellular Cascade
Depolarization → Ca²⁺ entry through voltage‑gated Ca²⁺ channels (Cav2.1, Cav2.2) → Ca²⁺ binding to synaptotagmin → SNARE complex assembly → vesicle fusion and exocytosis. Synaptotagmin acts as the Ca²⁺ sensor.
Required Cofactors
Ca²⁺ is essential for vesicle fusion. ATP is required for neurotransmitter reuptake and vesicle cycling.
Histology Stains
Immunohistochemistry for synaptophysin labels synaptic vesicles. Anti‑PSD95 labels postsynaptic densities in excitatory synapses.
EM Findings
Synaptic terminals contain clusters of small clear vesicles (40‑60 nm) for glutamate or GABA, and dense‑core vesicles for neuropeptides. Postsynaptic density appears as an electron‑dense thickening.
Knockout Phenotype
Knockout of synaptotagmin‑1 in mice abolishes fast synchronous neurotransmitter release and results in neonatal lethality due to respiratory failure.
Specific Toxins
Botulinum toxin (Botox) cleaves SNARE proteins (SNAP‑25, VAMP, syntaxin) blocking ACh release. Tetanus toxin cleaves VAMP in inhibitory neurons causing spastic paralysis. α‑Latrotoxin (black widow spider) causes massive neurotransmitter release.